The invention relates to novel compounds of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) (hereinafter referred to as xe2x80x9cformulae (I)-(VI)xe2x80x9d), which more particularly include sulfonylurea derivatives, sulfonylthiourea derivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidine derivatives, thioacylsulfonamide derivatives, and acylsulfonamide derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis.
Thrombotic complications are a major cause of death in the industrialized world. Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses. It is generally thought that platelet aggregates play a critical role in these events. Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus with disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion. Platelet activation can be initiated by a variety of agents, e.g., exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in the coagulation cascade.
An important mediator of platelet activation and aggregation is ADP (adenosine 5xe2x80x2-diphosphate) which is released from blood platelets in the vasculature upon activation by various agents, such as collagen and thrombin, and from damaged blood cells, endothelium or tissues. Activation by ADP results in the recruitment of more platelets and stabilization of existing platelet aggregates. Platelet ADP receptors mediating aggregation are activated by ADP and some of its derivatives and antagonized by ATP (adenosine 5xe2x80x2-triphosphate) and some of its derivatives (Mills, D. C. B. (1996) Thromb. Hemost. 76:835-856). Therefore, platelet ADP receptors are members of the family of P2 receptors activated by purine and/or pyrimidine nucleotides (King, B. F., Townsend-Nicholson, A. and Burnstock, G. (1998) Trends Pharmacol. Sci. 19:506-514).
Recent pharmacological data using selective antagonists suggests that ADP-dependent platelet aggregation requires activation of at least two ADP receptors (Kunapuli, S. P. (1998), Trends Pharmacol Sci. 19:391-394; Kunapuli, S. P. and Daniel, J. L. (1998) Biochem. J. 336:513-523; Jantzen, H. M. et al. (1999) Thromb. Hemost. 81:111-117). One receptor appears to be identical to the cloned P2Y1 receptor, mediates phospholipase C activation and intracellular calcium mobilization and is required for platelet shape change. The second platelet ADP receptor important for aggregation mediates inhibition of adenylyl cyclase. Molecular cloning of the gene or cDNA for this receptor has not yet been reported. Based on its pharmacological and signaling properties this receptor has been provisionally termed P2YADP (Fredholm, B. B. et al. (1997) TIPS 18:79-82), P2TAC (Kunapuli, S. P. (1998), Trends Pharmacol. Sci. 19:391-394) or P2Ycyc (Hechier, B. et al. (1998) Blood 92, 152-159).
Various directly or indirectly acting synthetic inhibitors of ADP-dependent platelet aggregation with antithrombotic activity have been reported. The orally active antithrombotic thienopyridines ticlopidine and clopidogrel inhibit ADP-induced platelet aggregation, binding of radiolabeled ADP receptor agonist 2-methylthioadenosine 5xe2x80x2-diphosphate to platelets, and other ADP-dependent events indirectly, probably via formation of an unstable and irreversible acting metabolite (Quinn, M. J. and Fitzgerald, D. J. (1999) Circulation 100:1667-1667). Some purine derivatives of the endogenous antagonist ATP, e.g., AR-C (formerly FPL or ARL) 67085MX and AR-C69931Mx, are selective platelet ADP receptor antagonists which inhibit ADP-dependent platelet aggregation and are effective in animal thrombosis models (Humphries et al. (1995), Trends Pharmacol. Sci. 16, 179; Ingall, A. H. et al. (1999) J. Med. Chem. 42, 213-230). Novel triazolo [4,5-d] pyrimidine compounds have been disclosed as P2T-antagonists (WO 99/05144). Tricyclic compounds as platelet ADP receptor inhibitors have also been disclosed in WO 99/36425. The target of these antithrombotic compounds appears to be the platelet ADP receptor mediating inhibition of adenylyl cyclase.
Despite these compounds, there exists a need for more effective platelet ADP receptor inhibitors. In particular, there is a need for platelet ADP receptor inhibitors having antithrombotic activity that are useful in the prevention and/or treatment of cardiovascular diseases, particularly those related to thrombosis.
The invention provides compounds of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI): 
A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and alkylheteroaryl.
W is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
E is selected from the group consisting of H, xe2x80x94C1xe2x80x94C8 alkyl, polyhaloalkyl, xe2x80x94C3-8cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, and substituted heteroaryl.
D is selected from the group consisting of NR1xe2x80x94(Cxe2x95x90O)xe2x80x94R2, xe2x80x94Oxe2x80x94R1; 
xe2x80x83wherein:
R1 is independently selected from the group consisting of:
H, C1xe2x80x94C8 alkyl, polyhaloalkyl, xe2x80x94C3-8-cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, substituted heteroaryl, xe2x80x94(Cxe2x95x90O)-C1xe2x80x94C8 alkyl, xe2x80x94(Cxe2x95x90O)-aryl, xe2x80x94(Cxe2x95x90O)-substituted aryl, xe2x80x94(Cxe2x95x90O)-heteroaryl and xe2x80x94(Cxe2x95x90O)-substituted heteroaryl;
R2 is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, or
R1 and R2 can be direct linked or can be indirectly linked through a carbon chain that is from 1 to about 8 carbon atoms in length,
n is 0-4,
m is 0 or 1,
y is 0-4 and
Q is independently C or N, with the proviso that when Q is a ring carbon atom, each ring carbon atom is independenty substituted by X.
X is in each case a member independently selected from the group consisting of:
H, halogen, polyhaloalkyl, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2R3, xe2x80x94C1-10-alkyl, xe2x80x94C3-8-cycloalkyl, aryl, aryl-substituted by 1-4 R3 groups, amino, amino-C1-8-alkyl, C1-3-acylamino, C1-3-acylamino-C1-8-alkyl, C1-6-alkylamino, C1-6-alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6-alkyl, carboxy-C1-6-alkyl, C1-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-6-alkyl, carboxy C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, and a 5 to 10 membered fused or non-fused aromatic or nonaromatic heterocyclic ring system, having 1 to 4 heteroatoms independently selected from N, O, and S, with the proviso that the carbon and nitrogen atoms, when present in the heterocyclic ring system, are unsubstituted, mono- or di-substituted independently with 0-2 R4 groups.
R3 and R4 are each independently selected from the group consisting of:
H, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94C1-10 alkyl, C3-8-cycloalkyl, aryl, amino, amino-C1-8-alkyl, C1-3-acylamino, C1-3-acylamino-C1-8-alkyl, C1-6-alkylamino, C1-6-alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6-alkyl, carboxy-C1-6-alkyl, C1-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-6-alkyl, carboxy-C1-6-alkyloxy, hydroxy, hydroxy-C1-6-alkyl, -thio and thio-C1-6-alkyl.
Y is selected from the group consisting of O, S, Nxe2x80x94OR5, and NR5,
wherein R5 is selected from the group consisting of:
H, C1-10 alkyl, C3-8-cycloalkyl, and CN.
The invention also covers all pharmaceutically acceptable salts and prodrugs of the compounds of formulae (I)-(VI).
In another aspect, the invention provides pharmaceutical compositions for preventing or treating thrombosis in a mammal containing a therapeutically effective amount of a compound of formulae (I)-(VI) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention further provides a method for preventing or treating thrombosis in a mammal by administering a therapeutically effective amount of a compound of formulae (I)-(VI) or a pharmaceutically acceptable salt thereof